The human monocytic cell lines MUTZ-3 and MONO-MAC-6 express the lipopolysaccharide (LPS) receptor CD14. Paralleling the situation in peripheral blood monocytes (PBMo), recombinant human interleukin-4 (IL-4) down-regulated the expression of CD14 on the cell surface of MUTZ-3, but not that of MONO-MAC-6 cells. In addition, preincubation with IL-4 prevented the LPS-induced up-regulation of IL-1 beta mRNA levels in MUTZ-3, but not in MONO-MAC-6 cells. We examined whether the differential responsiveness of the cell lines was due to the missing expression of the IL-4 receptor (IL-4R) alpha or gamma c chain in MONO-MAC-6 cells. Flow cytometric and immunoprecipitation analysis revealed expression of both IL-4R chains in both cell lines. In addition, short-term stimulation with IL-4 induced tyrosine-phosphorylation of the gamma c chain. As both cell lines also expressed signal transducer and activator of transcription 6 (STAT 6), our data suggested that the differential reaction patterns of MUTZ-3 and MONO-MAC-6 cells were not due to a generally defective IL-4R complex. Interestingly, long-term (48 hr) treatment with LPS rendered MONO-MAC-6 cells sensitive to IL-4. LPS up-regulated expression of monocyte-specific esterase (MSE) mRNA as well as CD14 protein in MONO-MAC-6 cells; both effects were inhibited by IL-4. This stimulation was not paralleled by an increase of IL-4R mRNA or protein expression supporting the above hypothesis of a constitutively present and active IL-4R. We discuss possible causes for the differential reaction patterns of MUTZ-3 and MONO-MAC-6 cells to IL-4.